Objective: The present study was designed to assess the immunohistochemical expression of GLUT-4 in tissue samples from patients with oral squamous cell carcinoma (OSCC), oral potentially malignant disorders (OPMDs) and normal oral mucosa to determine its role as a potential biomarker for oral malignancy and premalignancy. Materials and Methods: A total of 95 patients with OSCC (n=35), OPMDs (n=35) and healthy individuals (n=25) were included. Immunohistochemical staining was performed on paraffin-embedded tissue specimens. GLUT-4 immunoreactivity was determined and compared among the study participants and statistically analyzed at p<0.05 via SPSS version 20. Results: High Glut-4 immunoexpression was observed in all samples of normal oral mucosa (100%) followed by OSCC (80%) and OPMDs (57.14%). A highly significant (p=0.00046) difference was observed in the levels of Glut-4 Immunoexpression (low and high expression) among the study participants. Conclusion: Varied tissue immunoexpression of GLUT4 is observed in normal oral mucosa compared to lesions of OSCC and OPMDs. Immunohistochemical evaluation of GLUT4 can be a clinically important predictive marker for oral malignancy and premalignancy by differentiating between the lesions of OSCC and OPMDs and normal oral mucosa.